Prevention of CMV in Solid Organ Transplantation

Deepali Kumar MD MSc FRCP(C)Transplant Infectious Diseases

Multi-Organ Transplant ProgramUniversity Health Network

Disclosure

• Advisory Board: GSK, Pfizer, Atara, Qiagen, Oxford Immunotec

• Clinical Trial: GSK, Merck, Oxford Immunotec, Qiagen

• Honoraria: Shire, Merck, Pfizer

Objectives

• Examine the direct and indirect effects of CMV post-SOT

• Explore current and future approaches to CMV prevention

• Review case-based scenarios to illustrate various prevention approaches

CMV is the most common viral infection in SOT

• Genetic composition– 2 unique regions of DNA – UL and US

and flanking terminal repeat regions (TR) and internal repeat regions (IR)

– Encodes 168 + unique functional genes (exact number unknown)

– Gene expression occurs in a temporal cascade (IE, early, and late)

Crough, Clin Micro Rev 2009, Gandhi MK, Lancet ID 2004

What leads to CMV replication post-transplant

• Viral factors– Replication dynamics– Immune evasion– Viral heterogeneity– Viral co-infections

• Host factors– CD4+, CD8+ T-cell– NK cell, B-cell – Exogenous

immunosuppression – D/R serostatus

CMV PATHOGENESIS

Serologic Risk Profile for CMV

Risk Category Donor (D) / Recipient (R)Serologic Status (+/-)

High D+/R-

Intermediate* D+/R+, D-/R+

Low D-/R-

* D+/R+ generally at higher risk than D-/R+

Humar et al., AJT 2009; Fishman et al., Clin Transplant 2007

Effects of CMV Infection post-transplant

CMV Viral Syndrome• Fever, malaise, myalgias• Leukopenia, thrombocytopenia,

and other laboratory abnormalities

Tissue Invasive Disease• Hepatitis• Pneumonitis• Colitis• Carditis• Nephritis • Pancreatitis• Retinitis

Direct Effects

Indirect effects

Indirect Effects of CMV

Pro-inflammatory

effects

Immuno-suppressive

effects of viral infection

AlloreactivityDirect interaction

with other herpesviruses

Graft rejection; graft dysfunction

Opportunistic infections: Bacterial fungal superinfection

Decreased graft and patient survival

Herpesvirus interactions: EBV/PTLD

• 55 y.o. woman deceased donor kidney transplant CMV D+/R-

• ATG induction, is on Tac/Pred/MPA• For CMV prevention you would use:

• For CMV prevention you would use (adjusted for renal function)a) Valganciclovir 900mg/d x 3 months b) Valganciclovir 900mg/d x 6 monthsc) Preemptive strategy (VL monitoring)d) 3 months prophylaxis followed by pre-emptive

strategy

CMV PREVENTION: Universal Prophylaxis

• Antiviral therapy from the time of transplant to all patients or a subgroup of patients (3-6 months of antiviral prophylaxis in all D+/R-transplant patients)

• Prophylaxis very successful in multiple clinical trials for CMV prevention

RCT of oral GCV vs. VGCV

VGCV

Prophylaxis Period

GCV

% P

atie

nts

with

no

CM

V Vi

rem

ia

0

10

20

30

40

50

60

70

80

90

100

Time (days)0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

n=364 D+/R- kidney,liver,heart

Paya, et al AJT 2004

Viremia very common after prophylaxis

Impact Trial: RCT of 100d vs 200d VGCV

Valganciclovir 900 mg od*

Valganciclovir 900 mg od* Valganciclovir 900 mg od*

Placebo

100 days 200 daysRandomization 12 monthspost transplant

VGCV-100 days:

VGCV-200 days:

* dose adjusted for renal function

Humar A, et al. Am J Transplant. 201013

International RCTKidney recipients, D+/R-, N=316

Impact Trial

0

0.4

0.2

0

0.8

0.6

18060 120 240 360

1.0

300

Event-free probability

Study dayNumber of patients assessed

Valganciclovir 100 days 163 161 161 157 151 125 110 104 102 101 95 94 83 4

Valganciclovir 200 days 155 154 152 150 149 147 145 143 136 130 125 122 120 7

Valganciclovir 200 days

Valganciclovir100 days

CMV disease 36.8 vs 16.1% p<0.0001Higher rates of leukopenia (38% vs 26%)

Humar A, et al. Am J Transplant. 2010

• The patient is placed on Valganciclovir. At 2.5 months post-transplant the patient develops low WBC of 1.7 with ANC of 0.9. Septra is held. You woulda) Hold Valganciclovir b) Hold MPAc) Hold both a) and b) d) Not hold anything but give GCSF

Issues with Prophylaxis

1. Drug toxicity2. After discontinuation of prophylaxis – viremia

and disease often develops• “Late onset CMV disease”

– May present with atypical symptoms (no fever – malaise, fatigue); diagnosis can be missed

Maribavir• Inhibits UL97 (viral kinase)• Does not cover HSV / VZV• Some overlap with GCV-resistant mutations

Maribavir for CMV prophylaxis in D+/R- liver transplant

• RCT of GCV po 1g TID

vs. Maribavir 100mg

BID

• 307 patients

• Any CMV (disease or

infection) at 100 days:

20% vs. 60%, p<0.0001

• Any CMV at 6 months:

53% vs. 72%, p=0.005

Winston et al., AJT 2013

Letermovir• Terminase complex inhibitor

• Binds at UL56• Generally good safety profile• Drug interactions with CyA,

tacrolimus, voriconazole, others

• Covers CMV only • Need acyclovir for

HSV/VZV prevention• High-grade resistance

mutations in UL56 terminasegene are readily selected in vitro under letermovir; clinical correlation needed (not UL97/UL54) (Chou 2015)

Griffiths PD, et al. N Engl J Med. 2014;370(19):1844-1846. CyA, cyclosporine A; VZV, varicella zoster virus.

Letermovir Study: SOTKidney D+/R-

Arm 1

Arm 2

CMV Disease

CMV Disease

600 patientsNon-inferiority trialPlacebo controlledAcyclovir used in Letermovir arm

Letermovir 6 months 480 mg/d

Valganciclovir 6 months 900 mg/d

Clinicaltrials.gov

+_ + + + + ___ + + _

0 4 8 12 weeks

Could have initiated pre-emptive therapy

CMV disease

TEST

CMV PREVENTION: Pre-emptive Therapy

Either oral or IV can be used for pre-emptive therapy

133 130 128 123 123 124 124 122 118 115 117125 122 123 123 124 121 120 120 119 118 116

100000

10000

1000

100

100 7 14 21 28 35 42 49Days

Valganciclovir (N)IV Ganciclovir (N)

CM

V lo

ad (c

opie

s/m

L)

Treatment phase

Asberg A et al. Am J Transplant. 2007;7:2106-2113.

GCVVGCV

Issues with Pre-emptive therapy

• Weekly monitoring (needs patient compliance and physician review)

• Short viral doubling time in some patients

• Thresholds for treatment not established (likely different for D+/R- vs. R+)

• Effect of low level replication on graft not fully defined

Combination strategy: Surveillance after Prophylaxis

+ + + + + __ + + _

0 4 8 12 months

Could have initiated pre-emptive therapy

CMV disease

TEST

Prophylaxis

Prophylaxis Pre-emptiveEvidence of efficacy +++ ++

Indirect effects/mortality ++ +

Other viruses + for some -

Ease ++ +/-

Late onset disease ++ -

Resistance Low Low

Prophylaxis vs pre-emptive therapy

CMV Guidelines

AST Guidelines 2019, International Guidelines 2018

Serostatus Transplant Prophylaxis vs. Pre-emptive

Duration

D+/R- Kidney, liver, pancreas, heart

Universal prophylaxispreferredPreemptive strategy is an option

3-6 months6 months for kidneySome add CMVIg for heart

R+ Kidney, liver, pancreas, heart

Prophylaxis or pre-emptive therapy

3 months

D+/R- or R+ Lung Universal prophylaxis recommended

3-12 months for R+6-12 months for R-Some add CMV Ig

Prophylaxis versus Preemptive Therapy for the Prevention of CMV in High-Risk D+/R- Liver Transplant

Recipients

[CMV Antiviral Prevention Strategies In D+R- Liver Transplants (“CAPSIL”)]

Clinicaltrials.gov: NCT01552369

Objectives: To conduct a Phase II randomized controlled trial comparing prophylaxis with preemptive therapy using valganciclovir in D+/R- liver recipients with the primary endpoint of CMV disease. The secondary endpoints include: CMV-specific immunity, toxicity, and indirect outcomes.

Pre-emptive vs. Prophylaxis RCT

Singh et al. IDWeek Abstract LB21, 2018

N=205 D+/R- liver transplant patients randomized at 6 centersCMV disease: 9% in pre-emptive therapy and 19% in prophylaxis (p=0.04)

Stratifying Risk by CMV-specific Cell-mediated Immunity

Sester M, J Lab Med. 2008.

Assays based on measurement of IFN-γproduction by cells stimulated with CMV peptides, whole proteins or CMV whole virus

CMV D+/R-

Monitor CMI

Time Post-Transplant

Antiviral prophylaxis

D/C Prophylaxis

Prolong Prophylaxis or Monitor VL more

closely

+

-

CMI could be used to stratify who needs prophylaxis or pre-emptive therapy

CMV$viremia$detected$(≥1000$

IU/mL)$

An9viral$Therapy$(un9l$one$nega9ve$PCR$or$two$PCR$<137$IU/mL)$

CMV$CMI$Assay$at$End$of$An9viral$

Therapy$(within$48$hours)$

Nega9ve$CMI$An9viral$

prophylaxis$for$2$months$

Posi9ve$CMI$ No$An9viral$Prophylaxis$

APer$CMI$result:$•  CMV$viral$load$tes9ng$q2weeks$for$3$months$•  6$month$followup$

Am J Transplant 2017

An Interventional Study Using Cell Mediated Immunity to Personalize therapy for Cytomegalovirus infection after Transplantation Authors: Deepali Kumar, Muhtashim Mian, Lianne Singer, Atul Humar

CMI negative at end of therapy (n=13); Received additional 2 months of secondary prophylaxisBut still had a high rate of relapse

CMI positive at end of therapy (n=14); No secondary prophylaxisBut still had a low rate of relapse

CMV VaccinesAttenuated

Virus

• Towne/Toledo Chimeric• V160 replication defective

Recombinant Subunit or

Recombinant VLP

• gB/MF59• gB/ASO3• VBI-1501A

DNA vaccines• gB/pp65 (ASP0113)

Vectored vaccines

•Alphavax•HCMV – MVA (pp65, UL123 / IE-1 exon 4, UL122 / IE-1 exon 5)•HB-101 (gB, pp65)•Alvac – pp65

Peptide Vaccines

• CMV pp65 – T cell epitope fused to tetanus epitope

Anderholm et al. Drugs, 2016

Transplantation 2018

Clinical Transplantation 2019

Thank you!

• deepali.kumar@uhn.ca